Biomedical science often deals with objects so small that microscopes are needed to observe them. One of the most significant advancements in microscopy was the leap to using electrons instead of light to view samples. Driving this ground-breaking accomplishment in North America were two innovative graduate students, James Hillier and Albert Prebus, from the University of Toronto (Figure 1).
In 1665, Robert Hooke published Micrographia, a collection of illustrations of insects and plants as seen through an optical microscope (1). Hooke’s beautiful illustrations demonstrate the power of microscopy by shedding light on biological structures invisible to the naked eye (Figure 2). Over the course of the next two centuries, microscope technologies continue to be developed and used in science, though rarely straying from the usage of visible light to illuminate the sample of interest. This physically limited the ability of optical microscopes to resolve structures smaller than a few hundred nanometres, thus anything smaller than large compartment of cells, such as proteins, remained invisible to scientists.
The paradigm of optical microscopy would remain until the early 1900s, when Louis de Broglie hypothesized that electrons may possess wave-light properties similar to light (2). Since the wavelength of an electron is far smaller than that of a photon, a microscope using electrons to illuminate samples may be able to resolve finer details than a light microscope. After working out the principles of an electron lens, the first electron microscope was built by Ernst Ruska in Berlin in 1933 (3). Ruska would go on to share a Nobel Prize for his pioneering work in the field, but his first electron microscope could not resolve much better than an optical microscope. With other similar ventures in the world failing to produce high-quality images, many scientists became highly skeptical whether an electron microscope was even possible.
Amidst the skepticism, Eli F. Burton was convinced that electron microscopy could generate quality images at high resolution. Having recently been appointed as the Chairman of the Department of Physics at the University of Toronto, Burton found it difficult to retain graduate students to work on such an unpopular topic during the Great Depression. His first student, Cecil E. Hall, was paid only $800 to cover both his stipend and materials to build electron microscopes and ultimately had to leave the project due to lack of funding (4). Nevertheless, Hall and Burton were determined, and by 1936, Hall had built two electron microscopes that laid the foundation for James Hillier and Albert Prebus.
James Hillier received his bachelor's degree from the University of Toronto in 1937. He was later joined by Albert Prebus, a graduate from the University of Alberta who had changed his interests after being persuaded by Burton. With little more than Hall’s electron microscopes and the few publications on the subject that existed, Hillier and Prebus set out to engineer and construct a new, higher-resolution electron microscope. Working through their Christmas vacation in 1937, Hillier and Prebus constructed every component of their microscope from scratch, often working until 4:00am to build the perfect microscope that they envisioned (4) (Figure 3).
By April of 1938, the long hours hard work by Hillier and Prebus had paid off, when they were able to capture higher-quality images than ever before, having a resolution of ~60 Å, or approximately 40X higher than modern optical microscopes (Figure 4). Their successful design was soon implemented across North America, most significantly by Hillier to the Radio Corporation of America, which ultimately resulted in the first generation of practical and commercially available electron microscope in North America, selling approximately 2000 units between 1940 and the 1960s (5).
Since its invention, electron microscopy has enhanced and enabled many fields of biomedical research. This instrument has been fundamental to the fields of virology and phycology, by providing crucial insight into the morphology of virus particles and diatoms, respectively (6). It is also commonly used to capture sub-cellular structures in cells too small to be observed by other methods. Importantly, recent technological advances have further augmented the utility of electron microscopy in the study of protein structures. Today, structures of individual proteins and protein complexes can be accurately resolved at the atomic level, enabling scientists and companies like Cyclica to determine how drugs elicit their therapeutic or toxic effects at the molecular level. This knowledge allows for a comprehensive understanding of how one drug will interact with all proteins in the body, and provides rational decision-making that could not have been made using other techniques.
The electron microscope designed by Hillier and Prebus paved the way for future generations of electron microscopes and microscopists (the above timeline outlines notable achievements of Hillier, Prebus, and influencial figures in their life (Figure 5)), without which the many advancements in biomedical science and drug discovery that we take for granted would have been difficult to imagine. Cyclica honours the pioneering work and memories of James Hillier, Albert Prebus, Cecil E. Hall, and Eli F. Burton (Figure 6).
Stay tuned for our next blog outlining other great discoveries by Canadian scientists or check out our other blog posts for Canada150 found here.
1. Hooke, R. (1665) Micrographia. London: The Royal Society. Retrieved from http://www.gutenberg.org/files/15491/15491-h/15491-h.htm.
2. De Broglie, L. (1924) Recherches sur la théorie des Quanta. (Doctoral dissertation). Retrieved from TEL (00006807)
3. Ruska, E. (1934) Über ein magnetisches Objektiv für das Elektronenmikroskop. (Doctoral dissertation). Z Physik 89, 90-128.
4. Watson, H. L. (n.d.) The Electron Microscope, A Personal Recollection. Department of Physics at the University of Toronto, Toronto. Retrieved from https://www.physics.utoronto.ca/physics-at-uoft/history/the-electron-microscope/the-electron-microscope-a-personal-recollection.
5. Pearce, J. (2007, Jan. 22). James Hillier, 91, Dies; Co-Developed Electron Microscope. New York Times, pp. B8.
6. Burton, E. F., and Kohl, W. H. (1946) The Electron Microscope. An Introduction to its Fundamental Principles and Applications. New York: Reinhold.
This blog was written by Tonny Huang, a graduate student at the Princess Margaret Cancer Center. Tonny has a deep interest in the applications of protein science for the betterment of human health. You can find him here on LinkedIn.